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WO2015155306A1 - Nouveaux antagonistes de trpa1 - Google Patents

Nouveaux antagonistes de trpa1 Download PDF

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Publication number
WO2015155306A1
WO2015155306A1 PCT/EP2015/057764 EP2015057764W WO2015155306A1 WO 2015155306 A1 WO2015155306 A1 WO 2015155306A1 EP 2015057764 W EP2015057764 W EP 2015057764W WO 2015155306 A1 WO2015155306 A1 WO 2015155306A1
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propyl
acetamide
group
chlorophenoxy
pyrimidin
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Inventor
Nuria Aguilar Izquierdo
Maria Antonia Buil Albero
Stephen Connolly
Paul Robert Eastwood
Richard Spurring Roberts
Sara Sevilla Gomez
Bernat Vidal Juan
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Almirall SA
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Almirall SA
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds having TRPA1 activity.
  • This invention also relates to pharmaceutical compositions containing them, processes for their preparation and their use in the treatment of several disorders.
  • TRPA1 is a non-cation selective channel that belongs to the Transient Receptor Potential (TRP) superfamily.
  • TRP Transient Receptor Potential
  • TRPA1 was first identified from cultured lung fibroblasts (Jaquemar et al., 1999), and further studies indicated that TRPA1 was highly expressed in sensory neurons of the dorsal root, trigeminal and nodose ganglia. In sensory neurons, TRPA1 expression is most prevalent in small diameter neurons where it colocalizes with markers of peptidergic nociceptors such as TRPV1 , CGRP and substance P (Kaneko et al., 2013). Moreover, TRPA1 has been identified in the small intestine, colon, pancreas, skeletal muscle, heart, brain, and T and B- lymphocytes (Stokes et al., 2006).
  • TRPA1 is activated by a variety of noxious stimuli, including cold temperatures and pungent natural compounds (e.g., mustard, cinnamon and garlic). TRPA1 is also activated by environmental irritants, including isocyanates and heavy metals produced during the manufacturing of polymers, fertilizers, and pesticides. Vehicle exhaust, burning vegetation and electrophilic tear gases used as incapacitating agents, are potent activators of TRPA1 . TRPA1 antagonists or inhibitors could also have applications in defence against such agents.
  • noxious stimuli including cold temperatures and pungent natural compounds (e.g., mustard, cinnamon and garlic).
  • TRPA1 is also activated by environmental irritants, including isocyanates and heavy metals produced during the manufacturing of polymers, fertilizers, and pesticides. Vehicle exhaust, burning vegetation and electrophilic tear gases used as incapacitating agents, are potent activators of TRPA1 . TRPA1 antagonists or inhibitors could also have applications in defence against such agents.
  • TRPA1 is not only sensitive to electrophiles, but is also activated by oxidizing agents.
  • Reactive oxygen species ROS
  • ROS Reactive oxygen species
  • Reactive carbonyl species like 4- hydroxynonenal (4-HNE) and 4-oxononenal (4-ONE), resulting from lipid peroxidation act directly on TRPA1 .
  • ROS generated during inflammation excites airway sensory nerve fibres, and this response is largely reduced in TRPA1 -deficient mice.
  • TRPA1 activation is modulation by G protein-coupled receptors (GPCRs) through second-messenger signalling cascades.
  • GPCRs G protein-coupled receptors
  • Prostaglandin PGE2 and bradykinin (BK) are indirect activators of TRPA1 (Bessac, 2008).
  • TRPA1 has emerged as a key regulator of neuropeptide release and neurogenic inflammation.
  • TRPA1 is expressed in a subset of C-fibres that express TrkA and TRPV1 .
  • These afferent nerves have cell bodies in nodose, DRG and TG, and project to a variety of peripheral targets, including skin, airways, and gastrointestinal (Gl) tract.
  • TRPA1 role as a pain sensor is well-established.
  • a gain-of-function point mutation in TRPA1 was identified as the cause of Familial Episodic Pain Syndrome, a rare human pain disorder characterized by severe upper body pain triggered by fasting and physical stress (Kremeyer et al., 2010). Taming these hyperactive TRP channels by antagonists may prove clinically beneficial.
  • TRPA1 is required for the hypersensitivity that occurs in inflammatory pain models (Bautista et al. 2013, Julius 2013). TRPA1 expression is increased by inflammatory mediators such as NGF and following nerve injury or inflammation.
  • TRPA1 Activation of TRPA1 has been shown to cause pain and neurogenic inflammation.
  • Intrathecal TRPA1 antisense oligonucleotides administration suppressed inflammation and nerve injury-induced cold allodynia.
  • TRPA1 gene knock-out studies showed impaired sensory function to noxious cold, chemical and mechanical stimuli, suggesting that TRPA1 represents an important target for development of therapeutics for inflammatory and neuropathic pain conditions (Obata et al. 2003, McNamara et al. 2007, Petrus et al. 2007, Koivisto 2012).
  • TRPA1 is a promising target for the treatment of this chronic diabetic neuropathy associated with peripheral demyelination and the degeneration of nerve fibres.
  • TRPA1 may have a role in the pathogenesis of cancer and other inflammatory diseases. TRPA1 antagonists have been reported to revert oxaliplatin-induced neuropathic pain (Nativi, 2005).
  • TRPA1 Some anaesthetics, such as isoflurane or lidocaine, also activate TRPA1 , suggesting a possible role for TRPAI antagonists in post-surgical pain.
  • TRPA1 is implicated in migraine (Edelmayer et al., 2012), and dental pain (Haas et al., 201 1 ), as a result from neurogenic inflammation.
  • the activation of trigeminal TG neurons through nasal application of TRPA1 activators causes a CGRP-dependent increase in meningeal blood flow, that has been clinically shown to correlate with migraine headache.
  • TRPA1 could be considered a target for such conditions.
  • TRP channels are present in both neuronal and non-neuronal cells in the skin where they are thought to play a key role in itch, regulation of barrier function, keratinocyte differentiation, hair growth, inflammation, and wound healing (reviewed in Moran et al., 201 1 ).
  • TRPA1 is an essential component of the pathways that promote histamine- independent itch and may act as a downstream transduction channel onto which multiple pathways converge.
  • TRPA1 -/- mice to support a role for TRPA1 in the pathogenesis of different airway diseases including chronic cough, asthma, and COPD (Nassini et al., 2012b).
  • TRPA1 in the generation of irritant-induced cough reflexes.
  • Inhalation of a variety of TRPA1 agonists (acrolein, cinnamaldehyde, allyl isothiocyanate, crotonaldehyde) has been shown to produce a dose-dependent robust cough response in conscious guinea pigs and in humans (Andre et al., 2009; Birrell et al. , 2009).
  • Stimulating TRPA1 channels has been demonstrated to activate vagal bronchopulmonary C-fibres in the guinea pig and rodent lung.
  • TRPA1 agonists induced cough.
  • cough can be attenuated by TRPA1 inhibitors.
  • TRPA1 channels Antagonism of TRPA1 channels is expected to inhibit afferent nerve activation induced by cough stimulants, and represents an option for anti-tussive drugs development (Grace et al., 2012 and 2013). Moreover, patients treated with angiotensin-converting enzyme (ACE) inhibitors for hypertension have chronic cough as a side effect as result of heightened bradykinin levels. TRPA1 antagonists could represent an option to treat such side effects and chronic cough conditions.
  • ACE angiotensin-converting enzyme
  • TRPA1 -/- mice show little sign of lung inflammation, near- normal airway resistance, reduced eosinophil infiltration in the bronchi, and decreased production of proinflammatory cytokines and neuropeptides release in the airways, compared to TRPA1 +/+mice (Caceres et al., 2009). These studies point to TRPA1 as a promising target for the development of drugs aimed at treating the asthmatic response, allergen-induced airways inflammation, mucus production and airways hyper-reactivity.
  • CSE cigarette smoke extract
  • aldehydes increased Ca 2+ influx in
  • TRPA1 transfected cells and promoted neuropeptide release from isolated guinea pig airway tissue. Instillation of CSE into the trachea of wild-type mice and TRPA1 -/- mice only induced plasma protein extravasation in the wild type mice (Andree et al., 2008). These data suggest that targeting TRPA1 may have therapeutic potential in diseases caused by cigarette smoke such as COPD.
  • TRPA1 has been reported to have a critical role in mediating gastrointestinal (Gl) hypersensitivity to mechanical stimuli and serves as an important mediator of neuropeptide release triggered by inflammatory agents.
  • TRPA1 expression is elevated in the inflamed mouse gut (Yang et al., 2008; Izzo et al., 2012).
  • Experimental colitis induced by dinitrobenzene sulphonic acid (DNBS) was attenuated after both pharmacological blockade and genetic inactivation of TRPA1 (Engel et al., 201 1 ), pointing at potential of the target in Gl inflammatory conditions such as inflammatory bowel disease, Crohn's disease and ulcerative colitis, and colicky pain of Gl origin (Blackshaw et al., 2013).
  • TRPA1 is highly expressed in sensory neurons innervating bladder, urothelium, sub-urothelial space, muscle layers and around blood vessels (Streng et al. , 2008). Similar to TRPM8, TRPA1 is up-regulated in bladder mucosa in patients with bladder outlet obstruction (Du et al., 2008). TRPA1 agonists increased the micturition frequency models of cyclophosphamide-induced cystitis and spinal cord injury
  • TRPA1 antagonists could show potential for the treatment of bladder instability, urinary incontinence, and cystitis.
  • TRPA1 antagonists could show potential for the treatment of bladder instability, urinary incontinence, and cystitis.
  • TRPA1 antagonists could show potential for the treatment of bladder instability, urinary incontinence, and cystitis.
  • TRPA1 Several properties of TRPA1 make it an attractive drug target to treat inflammatory disorders; its ability to be activated by a large variety of endogenous and exogenous inflammatory compounds makes it an ideal detector of inflammatory cues, both in acute and in chronic conditions. Its peripheral expression of TRPA1 allows systemic, but also selective targeting of drugs by inhalation, ingestion, or topical application.
  • TRPA1 modulators of varied chemical structures have been recently disclosed for the treatment or prevention of chronic and acute inflammatory diseases and other pathological conditions, diseases and disorders known to be susceptible to amelioration by inhibition or antagonism of TRPA1 .
  • TRPA1 modulators of varied chemical structures have been recently disclosed for the treatment or prevention of chronic and acute inflammatory diseases and other pathological conditions, diseases and disorders known to be susceptible to amelioration by inhibition or antagonism of TRPA1 .
  • Several structural families of antagonists are observed. These include alcohols
  • Compounds having the capacity to selectively antagonise TRPA1 are in active development by several companies.
  • An example of these compounds is GRC-17536.
  • TRPA1 antagonists or inhibitors being suitable for the treatment of the above-mentioned diseases.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, a /V-oxide or a isotopically-labeled derivative thereof for use in the treatment of the human or animal body by therapy,
  • ⁇ G 1 is selected from the group consisting of a CH group and a N atom
  • G 2 is selected from the group consisting of a C(R a ) group and a N atom;
  • G 3 and G 4 are independently selected from the group consisting of a C atom and a N atom;
  • G 5 , G 6 and G 7 are independently selected from the group consisting of a C(R b ) group, a N(R C ) group, a N atom, an O atom and a S atom;
  • Q is a monocyclic or bicyclic C6-i 4 aryl or a monocyclic or bicyclic 5- to 14- membered heteroaryl ring, unsubstituted or substituted by one or more substituents selected from a linear or branched Ci -4 alkyl group, a halogen, a Ci -4 alkoxy group, a Ci -4 haloalkyl group, a Ci -4 haloalkoxy group, a cyano group, a hydroxyl group, an amino group, a Ci -4 monoalkylamino group, a Ci -4 dialkylamino group, a C3-7 cycloalkyl group, a phenyl ring and a phenoxy group;
  • R 1 and R 2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched Ci -4 alkyl group, a Ci -4 haloalkyl group, a C6-i 4 aryl group and a benzyl group; or R 1 together with the Q group, the O atom and the C atom where it is attached, form a fused bicyclic 8- to 14-membered heterocyclyl ring containing at least one heteroatom selected from O, S and N;
  • R 3 and R 4 are independently selected from the group consisting of a H atom and a F atom;
  • ⁇ R a is selected from the group consisting of a H atom, a linear or branched Ci -4 alkyl group, a halogen atom, a Ci -4 alkoxy group, a Ci -4 haloalkyl group, a Ci -4 haloalkyloxy group, a C3-7 cycloalkyl group, a cyano group, an amino group, a Ci- 4 monoalkylamino group and a Ci -4 dialkylamino group;
  • R b is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a C1-4 haloalkoxy group, an oxo group, a C3-7 cycloalkyl group, a cyan
  • R c is selected from the group consisting of a hydrogen atom, a linear or
  • n is an integer selected from 1 or 2;
  • • represents a single or a double bond.
  • the invention provides synthetic processes and intermediates described herein, which are useful for preparing compounds of the invention.
  • the invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically-acceptable carrier.
  • the invention further provides combinations comprising a compound of the invention and one or more other therapeutic agents and pharmaceutical compositions comprising such combinations.
  • the invention also provides a compound of the invention for use in the treatment of a disease or condition susceptible to amelioration by TRPA1 antagonists or inhibitors, in a mammal, in particular wherein the pathological condition or disease is selected from acute and/or chronic pain, acute and/or chronic pruritus, inflammatory
  • dermatological diseases respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders.
  • the invention also provides the use of a compound of the invention in the manufacture of a formulation or medicament for treating a disease or condition susceptible to amelioration by TRPA1 antagonists or inhibitors, in particular wherein the condition or disease is as described above.
  • the invention also provides a method of treating a disease or condition as described above; comprising such method administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the invention further provides a method of treatment comprising administering a therapeutically effective amount of a combination of a compound of the invention together with one or more other therapeutic agents.
  • C1-4 alkyl embraces unsubstituted or substituted, linear or branched radicals having 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, / ' -propyl, n-butyl, sec-butyl or i-butyl.
  • C1-4 alkoxy (or alkyloxy) embraces unsubstituted or substituted, linear or branched oxy-containing radicals each having alkyl portions of 1 to 4 carbon atoms.
  • Examples of C1-4 alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy and t-butoxy.
  • Ci-4 haloalkyl is a linear or branched alkyl group, which is substituted by one or more, preferably 1 , 2 or 3 halogen atoms. Examples include CCIs, CF 3 and CHF 2 .
  • Ci-4 haloalkoxy is typically a C1-4 alkoxy group substituted by one or more halogen atoms. Typically, it is substituted by 1 , 2 or 3 said halogen atoms. Examples of haloalkoxy groups include -OCF3 and -OCCI3.
  • C3-7 cycloalkyl embraces saturated carbocyclic radicals monocyclic or polycyclic ring having from 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Ce-14 aryl radical embraces typically a Ce-14, more preferably Ce- ⁇ monocyclic or bicyclic aryl radical such as phenyl, naphthyl, anthranyl and phenanthryl. Phenyl is preferred.
  • a said unsubstituted or substituted Ce-14 aryl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different. When a Ce-14 aryl radical carries 2 or more substituents, the substituents may be the same or different.
  • monocyclic or bicyclic 5- to 14-membered heteroaryl radical embraces typically a 5- to 14- membered ring system, preferably a 5- to 10- membered ring system, more preferably a 5- to 6-membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N.
  • a 5- to 14-membered heteroaryl radical may be a single ring or two fused rings wherein at least one ring contains a heteroatom.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl,
  • fused bicyclic 8- to 14-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated Ce-14 carbocyclic ring system, in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N , O and S.
  • the fused bicyclic 8- to 14-membered heterocyclyl group is formed by binding R 1 to the Q group, together with the O atom and the C atom where R 1 is attached, and therefore will always have an O atom in its structure.
  • Examples include benzo[c/][1 ,3]dioxolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b][1 ,4]dioxinyl, [1 ,3]dioxolo[4,5- b]pyridyl, 3,4-dihydro-2/-/-pyrano[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyrazyl, or 2,3- dihydro-[1 ,4]dioxino[2,3-b]pyridyl.
  • halogen atom embraces chlorine, fluorine, bromine or iodine atoms typically a fluorine, chlorine or bromine atom.
  • halo when used as a prefix has the same meaning.
  • Ci-4 rmonoalkylamino is represented by the formula -NH(Ci-4 alkyl) where Ci-4 alkyl is as described above.
  • Representative examples include methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, and (ieri-butyl)amino group.
  • C1-4 dialkylamino as used herein is represented by the formula - N(Ci-4 alkyl)2 where C1-4 alkyl is a described above.
  • Representative examples include dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group and d ⁇ tert- butyl)amino group.
  • terapéuticaally effective amount refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • treatment refers to the treatment of a disease or medical condition in a human patient which includes: (a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient;
  • pathological condition or disease susceptible to amelioration by inhibition or antagonism of TRPA1 includes all disease states and/or conditions that are acknowledged now, or that are found in the future, to be associated with an increased TRPA1 activity.
  • disease states include, but are not limited to, acute and/or chronic pain, acute and/or chronic pruritus, inflammatory dermatological diseases, respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders.
  • pain is used herein in the broadest sense and refers to all types of pain, including acute and chronic pain, such as nociceptive pain, e.g. somatic pain and visceral pain; inflammatory pain, dysfunctional pain, idiopathic pain, neuropathic pain, e.g., centrally generated pain and peripherally generated pain, migraine, and cancer pain.
  • nociceptive pain e.g. somatic pain and visceral pain
  • inflammatory pain e.g. somatic pain and visceral pain
  • idiopathic pain e.g., centrally generated pain and peripherally generated pain, migraine, and cancer pain.
  • the term "pruritus” is used herein in the broadest sense and refers to all types of itching and stinging sensations localized and generalized, acute intermittent and persistent.
  • the pruritus may be dermatologic, idiopathic, allergic, metabolic, infectious, drug-induced, due to liver, kidney disease, or cancer.
  • inflammatory dermatological disease includes the following dermatological diseases as non-limiting examples of such dermatological diseases: acne vulgaris, actinic keratosis, eczema, atopic dermatitis, insect bite inflammation, drug-induced skin reactions, psoriasis, rosacea and seborrheic dermatitis.
  • respiratory disorder any condition or disease related to respiration or the respiratory system and includes, but is not limited to, airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, bronchiectasis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), inflammatory respiratory diseases conditions poorly responder to corticosteroids (i.e. severe COPD and asthma)", sensory hyper-reactivity, multiple chemical sensitivity, and aid in smoking cessation therapy.
  • corticosteroids i.e. severe COPD and asthma
  • cough refers to both acute and/or chronic cough and includes interstitial lung disease cough, post-viral cough, gastroesophageal reflux disease (GERD)-related cough, cough variant asthma, COPD cough, lung cancer cough, upper airways cough syndrome (UACS), post nasal drip cough, idiopathic cough or cough associated with other respiratory diseases such as idiopathic pulmonary fibrosis (IPF).
  • GFD gastroesophageal reflux disease
  • COPD COPD cough
  • UACS upper airways cough syndrome
  • IPF idiopathic cough or cough associated with other respiratory diseases such as idiopathic pulmonary fibrosis
  • gastrointestinal inflammatory disorders includes, but is not limited to, disorders such as inflammatory bowel disease, ulcerative colitis or Crohn's disease.
  • urinary tract disorders includes, but is not limited to, disorders such as urinary incontinence, bladder instability or cystitis.
  • pharmaceutically-acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal.
  • Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
  • Salts derived from pharmaceutically-acceptable acids include acetic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, hydrofluoric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic (1 -hydroxy-2-naphthoic acid), napadisilic (1 ,5-naphthalenedisulfonic acid), triphenyl acetic and the like.
  • salts derived from formic, fumaric, hydrobromic, hydrochloric, hydrofluoric, acetic, sulfuric, methanesulfonic, xinafoic, tartaric, maleic, succinic and napadisilic acids are particularly preferred.
  • Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of ammonia, primary, secondary and ie fiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as ammonia, arginine, betaine, caffeine, choline, /V,/V-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, /V-ethylmorpholine, /V-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • X " may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
  • organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • X " is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X " is chloride, bromide, trifluoroacetate or methanesulphonate.
  • an /V-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • solvate means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
  • solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
  • solvent is water
  • hydrate is used instead of solvate.
  • the invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l , nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, 3 H, and carbon-14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 0 and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • Preferred isotopically-labeled compounds include deuterated derivatives of the compounds of the invention.
  • deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium (D or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • Hydrogen deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial.
  • a deuterated derivative of a compound of the invention has an isotopic enrichment factor (ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation).
  • isotopic enrichment factor ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen
  • the isotopic enrichment factor is at least 5000 (75% deuterium). In a more preferred embodiment, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In a most preferred embodiment, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent from the other deuteration sites.
  • the isotopic enrichment factor can be determined using conventional analytical methods known too en ordinary skilled in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR).
  • MS mass spectrometry
  • NMR nuclear magnetic resonance
  • the compounds of the invention may contain one or more chiral centers. Accordingly, the invention includes racemic mixtures, enantiomers, and mixtures enriched in one or more stereoisomer.
  • the scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
  • the invention provides with a compound or a pharmaceutically acceptable salt, a /V-oxide or a isotopically-labeled derivative thereof of formula (I)
  • G 1 is selected from the group consisting of a CH group and a N atom
  • G 2 is selected from the group consisting of a C(R a ) group and a N atom;
  • G 3 and G 4 are independently selected from the group consisting of a C atom and a N atom;
  • G 5 , G 6 and G 7 are independently selected from the group consisting of a C(R b ) group, a N(R C ) group, a N atom, an O atom and a S atom;
  • Q is a monocyclic or bicyclic C6-i 4 aryl or a monocyclic or bicyclic 5- to 14- membered heteroaryl ring, unsubstituted or substituted by one or more substituents selected from a linear or branched Ci -4 alkyl group, a halogen, a Ci -4 alkoxy group, a Ci -4 haloalkyl group, a Ci -4 haloalkoxy group, a cyano group, a hydroxyl group, an amino group, a Ci -4 monoalkylamino group, a Ci -4 dialkylamino group, a C3-7 cycloalkyl group, a phenyl ring and a phenoxy group;
  • R 1 and R 2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched Ci -4 alkyl group, a Ci -4 haloalkyl group, a C6-i 4 aryl group and a benzyl group; or R 1 together with the Q group, the O atom and the C atom where it is attached, form a fused bicyclic 8- to 14-membered heterocyclyl ring containing at least one heteroatom selected from O, S and N;
  • R 3 and R 4 are independently selected from the group consisting of a H atom and a F atom;
  • R a is selected from the group consisting of a H atom , a linear or branched Ci -4 alkyl group, a halogen atom, a Ci -4 alkoxy group, a Ci -4 haloalkyl group, a Ci -4 haloalkyloxy group, a C3-7 cycloalkyl group, a cyano group, an amino group, a Ci-4 rmonoalkylamino group and a Ci-4 dialkylamino group;
  • R b is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom, a Ci-4 alkoxy group, a Ci-4 haloalkyl group, a C1-4 haloalkoxy group, an oxo group, a C3-7 cycloalkyl group, a cyano group, an amino group, a Ci-4 rmonoalkylamino group, a Ci-4 dialkylamino group and a hydroxyl group;
  • R c is selected from the group consisting of a hydrogen atom, a linear or
  • ⁇ n is an integer selected from 1 or 2;
  • Q represents a phenyl group or a pyridine group, unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a linear or branched C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 haloalkyl group, a C1-4 haloalkoxy group, a cyano group, a C1-4 dialkylamino group, a phenyl ring and a phenoxy group.
  • substituents selected from the group consisting of a halogen atom, a linear or branched C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 haloalkyl group, a C1-4 haloalkoxy group, a cyano group, a C1-4 dialkylamino group, a phenyl ring and a phenoxy group.
  • R 1 and R 2 are independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group; or R 1 together with the Q group, the O atom and the C atom where it is attached form a fused bicyclic ring of formula (a), (b), (c) or (d).
  • G 1 represents a CH group and G 2 represents a N atom.
  • G 5 , G 6 and G 7 are independently selected from the group consisting of a C(R b ) group, a N(R C ) group and a N atom.
  • G 1 -G 7 are not all N atoms.
  • R b is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom and a C1-4 alkoxy group; preferably a H atom, a halogen atom, a methyl group and a methoxy group.
  • G 1 represents a CH group and G 2 represents a N atom;
  • G 5 , G 6 and G 7 are independently selected from the group consisting of a C(R b ) group, a N(R C ) group and a N atom;
  • Q represents a phenyl group or a pyridine group, unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a linear or branched C1-4 alkyl group, a C1-4 alkoxy group, a Ci-4 haloalkyl group, a Ci-4 haloalkoxy group, a cyano group, a Ci-4 dialkylamino group, a phenyl ring and a phenyloxy group;
  • R 1 and R 2 are independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group; or R 1 together with the Q group, the O atom and the C atom where it is attached form a fused bicyclic ring of formula (a), (b), (c) or (d);
  • R b is selected from the group consisting of a H atom, a linear or branched C1-4 alkyl group, a halogen atom and a C1-4 alkoxy group; preferably a H atom, a halogen atom, a methyl group and a methoxy group.
  • Particular individual compounds of the invention include:
  • the compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions are given (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and de-protection, are well known in the art. For example, numerous protecting groups, and their introduction and removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • Compounds of general formula (I) may be prepared from bicyclic compounds of formula (2) wherein A is equivalent to a bicyclic group wherein G 1 -G 7 and n are as defined in Claim 1 , and an alkylating agent of formula (3) wherein W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para- toluenesulphonate or methylsulfonate and R 1 -R 4 and Q are as defined in Claim 1 .
  • the reaction is carried out by mixing a compound of formula (2) and compound of formula (3) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from ambient to 80 °C.
  • Compounds of general formula (5) wherein A is as hereinbefore defined and R 10 represents an alkyl group such as methyl, ethyl, propyl, ie f-butyl, benzyl or 2- (trimethylsilyl)ethyl may be prepared from bicyclic compounds of formula (2) and an alkylating agent of formula (4) wherein W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate.
  • the reaction is carried out by mixing a compound of formula (2) and compound of formula (4) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from ambient to 80 °C.
  • Compounds of general formula (6) wherein A is as hereinbefore defined may be prepared from compounds of formula (5) wherein R 10 is as hereinbefore defined by hydrolysis according to standard literature methods known to those skilled in the art of ester hydrolysis.
  • this may be through the use of a base such as sodium hydroxide in a solvent such as water, methanol, ethanol or tetrahydrofuran, or mixtures thereof, at a temperature from ambient to 50 °C.
  • a base such as sodium hydroxide in a solvent such as water, methanol, ethanol or tetrahydrofuran, or mixtures thereof, at a temperature from ambient to 50 °C.
  • an acid such as hydrochloric acid or trifluoroacetic acid in water, dichloromethane, chloroform or dioxane or a mixture thereof at a temperature from ambient to 50 °C.
  • Compounds of general formula (I) may be prepared from compounds of formula (6) wherein A is as hereinbefore defined and an amine of formula (7) wherein R 1 - R 4 and Q are as defined in Claim 1 , in the presence of a peptide coupling reagent such as dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), in the presence or absence of a catalyst such as 1 -hydroxybenzotriazole (HOBt).
  • DCC dicyclohexylcarbodiimide
  • EDC 1 -ethyl-3-(3-dimethylaminopropyl)-carbodiimide
  • HOBt 1 -hydroxybenzotriazole
  • a carboxylic acid of formula (6) and an amine of formula (8) in the presence of a peptide coupling reagent such as dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDO) or benzotriazolyloxy-tris[pyrrolidino]- phosphonium hexafluorophosphate (PyBOP).
  • DCC dicyclohexylcarbodiimide
  • EEO 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • PyBOP benzotriazolyloxy-tris[pyrrolidino]- phosphonium hexafluorophosphate
  • Compounds of general formula (I) may be prepared from compounds of formula (9) and a hydroxyl compound of formula (10), wherein Q is as hereinbefore defined.
  • the reaction is carried out in the presence of a base such as caesium carbonate or potassium carbonate in a solvent such as dimethylformamide at a temperature from ambient to 100 °C.
  • compounds of formula (I) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with a hydrogen atom may be converted to a compound of formula (I) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with a halogen atom such as chlorine, bromine or iodine.
  • the reaction may be carried out by mixing a compound of formula (I) with a halogenating reagent such as copper(ll) bromide, N- chlorosuccinimide, /V-bromosuccinimide, /V-iodoosuccinimide, bromine or iodine, in a solvent such as acetonitrile, chloroform or dimethylformamide at a temperature from 0 °C to the boiling point of the solvent.
  • a halogenating reagent such as copper(ll) bromide, N- chlorosuccinimide, /V-bromosuccinimide, /V-iodoosuccinimide, bromine or iodine
  • compounds of formula (2) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with a hydrogen atom may be converted to a compound of formula (2) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with a halogen atom such as chlorine, bromine or iodine.
  • the reaction may be carried out by mixing a compound of formula (I) with a halogenating reagent such as copper(ll) bromide, /V-chlorosuccinimide, /V-bromosuccinimide, /V-iodoosuccinimide, bromine or iodine, in a solvent such as acetonitrile, chloroform or dimethylformamide at a temperature from 0 °C to the boiling point of the solvent.
  • a halogenating reagent such as copper(ll) bromide, /V-chlorosuccinimide, /V-bromosuccinimide, /V-iodoosuccinimide, bromine or iodine
  • compounds of formula (I) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with a chlorine atom, a bromine atom or an iodine atom, herein referred to as a halogenated derivative may be converted to other compounds of formula (I) wherein groups G 5 , G 6 or G 7 which were previously substituted with a halogen atom are now substitiuted with an alkyl group, a cycloalkyl group or a haloalkyl group such as methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl or trifluoromethyl.
  • the halogenated derivative is treated with an organometallic reagent wherein the metal is selected from lithium or salts or complexes of magnesium, zinc, copper, tin or boron.
  • the reaction is carried out by treating the halogenated derivative according to standard literature methods known to those skilled in the art of carbon-carbon cross-coupling reactions.
  • the reaction can be carried out by treating the halogenated derivative with a trialkylboroxine reagent in the presence of a transition metal catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]-dichloropalladium(ll), in the presence of a base such as potassium carbonate, in a solvent such as dioxane at a temperature from ambient to 150 °C under an inert atmosphere such as argon.
  • a transition metal catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]-dichloropalladium(ll)
  • a base such as potassium carbonate
  • compounds of formula (2) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with a chlorine atom, a bromine atom or an iodine atom, herein referred to as halogenated derivative may be converted to other compounds of formula (I) wherein groups G 5 , G 6 or G 7 which were previously substituted with a halogen atom are now substitiuted with an alkyl group, a cycloalkyl group or a haloalkyl group such as methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl or trifluoromethyl.
  • the halogenated derivative is treated with an organometallic reagent wherein the metal is selected from lithium or salts or complexes of magnesium, zinc, copper, tin or boron.
  • the reaction is carried out by treating the halogenated derivative according to standard literature methods known to those skilled in the art of carbon- carbon cross-coupling reactions.
  • the reaction can be carried out by treating a halogenated derivative with a trialkylboroxine reagent in the presence of a transition metal catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]- dichloropalladium(ll), in the presence of a base such as potassium carbonate, in a solvent such as dioxane at a temperature from ambient to 150 °C under an inert atmosphere such as argon.
  • a transition metal catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]- dichloropalladium(ll)
  • a base such as potassium carbonate
  • compounds of formula (I) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with an alkoxy group such as methoxy or ethoxy may be converted to other compounds of formula (I) wherein groups G 5 , G 6 or G 7 which were previously substituted with an alkoxy group are now substitiuted with a hydroxyl group.
  • the reaction is carried out by treating a compound of formula (I) with a metal halide reagent such as boron tribromide, trimethylsilyl chloride, sodium iodide, or mixtures thereof in a solvent such as dioxane at a temperature from ambient to 150 °C under an inert atmosphere such as argon.
  • compounds of formula (2) wherein one or more of the groups G 5 , G 6 or G 7 is substituted with an alkoxy group such as methoxy or ethoxy may be converted to other compounds of formula (2) wherein groups G 5 , G 6 or G 7 which were previously substituted with an alkoxy group are now substitiuted with a hydroxyl group.
  • the reaction is carried out by treating a compound of formula (2) with a metal halide reagent such as boron tribromide, trimethylsilyl chloride, sodium iodide, or mixtures thereof in a solvent such as dioxane at a temperature from ambient to 150 °C under an inert atmosphere such as argon.
  • Compounds of general formula (2) wherein G 1 is a CH group and G 2 is nitrogen may be prepared from compounds of formula (1 1 ) wherein R 11 represents hydrogen atom or an alkyl group such as methyl, ethyl, propyl, ie f-butyl or benzyl, and a formamide equivalent such as formamide or formamidine and salts thereof.
  • R 11 represents hydrogen atom or an alkyl group such as methyl, ethyl, propyl, ie f-butyl or benzyl, and a formamide equivalent such as formamide or formamidine and salts thereof.
  • R 11 is a hydrogen atom
  • the reaction is carried out by mixing a compound of formula (1 1 ) with formamide in the presence or absence of an acid such as acetic acid at a temperature from 50°C to the boiling point of the solvent to give a compound of formula (2).
  • reaction is carried out by mixing a compound of formula (1 1 ) with formamidine acetate in the presence or absence of an acid such as acetic acid at a temperature from 50°C to the boiling point of the solvent to give a compound of formula (2).
  • an acid such as acetic acid
  • Compounds of general formula (2) wherein G 1 is a CH group and G 2 is nitrogen may also be prepared from compounds of formula (12), wherein G 3 - G 7 and n are as defined in Claim 1 , and an o f/?o-formate of formula (13) wherein R 12 represents an alkyl group such as methyl or ethyl, in the presence or absence of a solvent such as acetic anhydride at a temperature from ambient to the boiling point of the solvent.
  • Intermediates of formula (15) may be prepared from compound of formula (14) and a doubly activated carbonyl reagent such as phosgene, triphosgene or carbonyl diimidazole in a solvent such as dioxane at a temperature from 0 °C to the boiling point of the solvent.
  • a doubly activated carbonyl reagent such as phosgene, triphosgene or carbonyl diimidazole
  • R 10 represents an alkyl group such as methyl, ethyl, propyl, ie f-butyl, benzyl or 2-(trimethylsilyl)ethyl
  • R 10 is as hereinbefore defined in the presence of a base such as triethylamine and in a solvent such as dioxane at a temperature from 0 °C to the boiling point of the solvent.
  • Intermediates of formula (5) wherein R 10 is as hereinbefore defined may be prepared from compounds of formula (17) by diazotization with a reagent such as sodium nitrite or isoamyl nitrite in the presence of an acid such as acetic acid in a solvent such as water.
  • a reagent such as sodium nitrite or isoamyl nitrite in the presence of an acid such as acetic acid in a solvent such as water.
  • Intermediates of the general formula (3) may also be prepared following the synthetic scheme depicted in Scheme 4.
  • the reaction is carried out by treating a compound of formula (18) with a compound of formula (10) in the presence of a dialkyi azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and a phosphine such as triphenylphosphine, in a solvent such as tetrahydrofuran, at a temperature from 0 °C to 50 °C.
  • a dialkyi azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD)
  • a phosphine such as triphenylphosphine
  • R 1 -R 4 , Q and PG-N are as hereinbefore may also be prepared from compounds of formula (20) wherein R 1 -R 4 and N-PG are as hereinbefore defined and W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate.
  • the reaction is carried out by treating a compound of formula (20) with a compound of formula (10) in the presence of a base such as caesium carbonate in a solvent such as dimethylformamide at a temperature from ambient to 100 °C.
  • R 1 -R 4 , Q and W 1 are as hereinbefore defined may be prepared from compounds of formula (7) and an acyl halide of formula (21 ) wherein W 1 is as hereinbefore defined and W 2 represent a halogen atom such as fluorine, chlorine or bromine.
  • the reaction is carried out by treating a compound of formula (7) with a compound of formula (21 ) in the presence of a base such as triethylamine in a solvent such as dichloromethane at a temperature from 0 °C to 50 °C.
  • Reagents, starting materials, and solvents were purchased from commercial suppliers and used as received. Commercial intermediates are referred to in the experimental section by their lUPAC name. Ether refers to diethyl ether, unless otherwise specified. Concentration or evaporation refer to evaporation under vacuum using a Buchi rotatory evaporator.
  • Reaction products were purified, when necessary, by flash chromatography on silica gel (40-63 ⁇ ) with the solvent system indicated. Purifications in reverse phase were made in a Biotage Isolera® automated purification system equipped with a C18 column and using a gradient, unless otherwise stated, of water-acetonitrile/MeOH (1 :1 ) (0.1 % v/v ammonium formate both phases) from 0% to 100% acetonitrile/MeOH (1 :1 ) in 40 column volumes.
  • the conditions "formic acid buffer” refer to the use of 0.1 % v/v formic acid in both phases.
  • the appropriate fractions were collected and the solvents evaporated under reduced pressure and/or liofilized.
  • Preparative H PLC-MS were performed on a Waters instrument equipped with a 2767 injector/collector, a 2525 binary gradient pump, a 2996 PDA detector, a 515 pump as a make-up pump and a ZQ4000 Mass spectrometer detector.
  • the chromatographic separations were obtained using a Waters 2795 system equipped with a Symmetry C18 (2.1 x 50 mm, 3.5 ⁇ ) column for methods A, B and C and a Symmetry C18 (2.1 x 100 mm, 3.5 ⁇ ) for method D.
  • the mobile phases were (B): formic acid (0.4 ml), ammonia (0.1 ml), methanol (500 ml) and acetonitrile (500 ml) and (A): formic acid (0.5 ml), ammonia (0.125 ml) and water (1000 ml) (A), the gradients are specified in the following table for each method used.
  • the flow rate was 0.8 ml/min for method A and 0.4 ml/min for method B, C and D.
  • the injection volume was 5 microliter.
  • a Waters 2996 diode array was used as a UV detector.
  • Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization in a Micromass ZMD or in a Waters ZQ detectors coupled to the HPLC.
  • the UPLC chromatographic separations were obtained using a Waters Acquity UPLC system coupled to a SQD mass spectrometer detector.
  • the system was equipped with an ACQUITY UPLC BEH C-18 (2.1x50mm, 1 .7 mm) column.
  • the mobile phase was formic acid (0.4 ml), ammonia (0.1 ml), methanol (500 ml) and acetonitrile (500 ml) (B) and formic acid (0.5 ml), ammonia (0.125 ml) and water (1000 ml) (A).
  • a gradient between 0 to 95% of B was used.
  • the run time was 3 or 5 minutes.
  • the injection volume was 0.5 microliter.
  • Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization. Preparative HPLC was carried out on an Agilent 1200 Series (AE-0010) with diode array detection and peak collection. Specific details are mentioned in the experimental section.
  • Triethylamine (0.42 mL, 3.0 mmol) was added dropwise to a stirred suspension of the title compound of PREPARATION 8 (0.192 g, 0.96 mmol) and ie/f-butyl 2- aminoacetate hydrochloride salt (0.169 g, 1 .01 mmol) in 1 ,4-dioxane (9 mL). After 20 h, the mixture was filtered and the filter cake was washed with a little 1 ,4-dioxane. The combined filtrate and washings was evaporated to give 0.27 g of the crude product which was used without further purification in the next synthetic step.
  • Oxalyl chloride (0.10 mL, 1 .15 mmol) and /V,/V-dimethylformamide (2 drops) were added to a stirred suspension of the title compound of PREPARATION 13 (0.200 g, 0.83 mmol) in dry dichloromethane (5 mL) and the mixture was stirred overnight at ambient temperature. Further oxalyl chloride (0.05 mL) was added and stirring was continued for a further 4 h before the mixture was evaporated in vacuo.
  • the reaction mixture was allowed to cool to ambient temperature, diluted with ethyl acetate (75 mL) and washed with a saturated aqueous sodium hydrogen carbonate solution (50 mL) and water (2 x 50 mL). The combined organic extracts were dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The crude residue was purified by column chromatography (Biotage SNAP 50 g column, MeOH-dichloromethane gradient, 0:100 rising to 10:90) to give 452 mg of the title compound (1 .40 mmol, 57%) as a white solid.
  • the title compound of PREPARATION 62 (0.57 g, 3.80 mmol) was suspended in 12 ml dimethylformamide. /V-Bromosuccinimide (1 .49 g. 8.37 mmol) was added and the mixture was stirred at 80 °C for 16 h. The mixture was allowed to cool and was partitioned between water and ethyl acetate, forming a precipitate in the organic phase. The solid was collected by filtration and was dried in vacuo at 35 °C to give 0.50 g of the title compound (2.18 mmol, 57%) as a white solid.
  • the title compound was synthesized from the title compound of PREPARATION 65 according to the method described in Heim-Riether and Healy, J. Org. Chem. 2005, 70, 7331 .
  • N-methyl-3-oxobutanamide (400 mg, 2.43 mmol) and malonitrile (160 mg, 2.43 mmol) were suspended in 10 mL of ethanol. Five drops of piperidine were added and the mixture was stirred and heated at 80°C overnight. The mixture was then cooled to ambient temperature and was concentrated in vacuo. The residue was purified by flash chromatography using the Isolera purification system (ethyl acetate-hexane gradient, 0:100 rising to 100:0) to give 95 mg (0.58 mmol, 24% yield) of the title compound as a yellow solid. Purity 100%.
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ ppm 7.40 (s, 2 H), 5.58 (s, 1 H), 3.28 (s, 3 H), 2.10 (s, 3 H).
  • Diethyl 2-fluoromalonate (15 g, 84 mmol) was suspended in 50 mL of methanol. A solution of potassium hydroxide (5.6 g, 84 mmol) in 40 mL of methanol was added and the mixture was stirred at room temperature for 2.5h. Benzylamine (27.6 mL, 250 mmol) was added and the mixture was stirred and heated at 55°C overnight. The mixture was cooled to ambient temperature and was concentrated in vacuo. The residue was triturated with ether to give a solid which was collected by filtration and washed with ether. The solid was partitioned between 5N hydrochloric acid and ethyl acetate.
  • the mixture was then heated at 55°C overnight.
  • the mixture was cooled to ambient temperature and water and an 5N aqueous hydrochloric acid were carefully added.
  • PREPARATION 81 tert-Butyl (2-fluoro-3-hydroxypropyl)carbamate
  • the title compound of PREPARATION 80 (10.9 g, 59 mmol) was suspended in 250 mL of methanol and 10% Palladium on carbon (5.4 g) wet with 5.5 mL of water was added, ammonium formate (18.8 g, 300 mmol) was added in portions and the mixture was stirred and heated at 55°C for 2h. The reaction was cooled to ambient temperature and filtered through Celite® eluting with methanol. The organic extract was evaporated under reduced pressure. The residue was re-dissolved in water and was adjusted to pH 3-4 with 5N hydrochloric acid.
  • the aqueous phase was extracted with ethyl acetate and basified to pH 9-10 with 32% potassium hydroxide solution.
  • a solution of di-tert-butyl dicarbonate (13.0g 75 mmol) in 25 mL tetrahydrofuran was added drop-wise and the mixture was stirred at room temperature for 24h.
  • the phases were separated and the aqueous layer was extracted with ethyl acetate.
  • the combined organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure.
  • PREPARATION 88 8-Methylisoquinolin-1 (2H)-one
  • the title compound of PREPARATION 87 (276 mg, 1 .73 mmol) was dissolved in 5 mL acetic anhydride and the mixture was refluxed for 4h. The solvent was evaporated under reduced pressure. 1 M Sodium hydroxide solution (5 mL, 5 mmol) was added and the mixture was heated at 80 °C overnight. The reaction was cooled to room temperature and dichloromethane was added. The phases were separated and the aqueous layer was extracted with dichloromethane. The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure.
  • PREPARATION 92 tert-Butyl (5-methyl-4-oxo-1 ,2,3-benzotriazin-3(4H)-yl)acetate Synthesized from the title compound of PREPARATION 91 . Yield: 84%. Purity 94%.
  • Methyl 4-methyl-1 H-pyrazole-5-carboxylate (1 .36 g, 9.7 mmol) was dissolved in 70 ml anhydrous DMF under nitrogen and the solution cooled to -10 °C.
  • Lithium bis(trimethylsilyl)amide solution (1 M in tetrahydrofuran, 10.7 ml, 10.7 mmol) was added dropwise with stirring over 15 min.
  • O- (dipenylphosphoryl)hydroxylamine (2.73 g, 1 1 .7 mmol) was added and the mixture was stirred for 10 min at -10 °C and then 1 h at room temperature, forming a solid mass.
  • 6-Chloro-N-methylpyrimidin-4-amine 4,6-Dichloropyrimidine (10 g, 67 mmol) was dissolved in 100 ml isopropanol and the solution was cooled to 0 °C, reprecipitating.
  • Methylamine solution (33% w/w, 17 ml, 140 mmol) was added slowly with stirring and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure. The residue was resuspended in water, stirred for 15 min and then filtered. The solid was dried under reduced pressure. The filtrate was extracted three times with ethyl acetate. The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The solid obtained was combined with the first precipitate to give 8.50 g (59 mmol, 88% yield) of the title as a white solid. Purity 87%.
  • the title compound of PREPARATION 97 (8.5 g, 59 mmol) was dissolved in 100 ml methanol. Sodium methoxide (19.8 g, 370 mmol) was added in several portions over a 4 day period while the mixture was stirred at reflux. The mixture was allowed to cool and was evaporated under reduced pressure. The solid residue was resuspended in dichloromethane and was stirred for 1 h. The solution was filtered and the filtrate was evaporated under reduced pressure to give 7.80 g (56 mmol, 95% yield) of the title compound as a white solid. Purity 100%.
  • PREPARATION 104 tert-Butyl (7,9-dimethyl-6,8-dioxo-6,7,8,9-tetrahydro-1 H-purin-1 -yl)acetate
  • the title compound of PREPARATION 103 (180 mg, 0.64 mmol) was dissolved in 4 ml dimethylformamide and the solution was cooled to 0°C in an ice-bath.
  • Sodium hydride (60% suspension in oil, 41 mg, 1 .0 mmol) was added and the mixture was stirred for 30 min.
  • Methyl iodide (42 ⁇ , 0.67 mmol) was added and the mixture was stirred overnight, warming to room temperature.
  • the mixture was partitioned between ethyl acetate and water. The organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated to give 190 mg (0.64 mmol, 100% yield) of the title compound as a yellow oil. Purity
  • PREPARATION 106 tert-Butyl (1 , 3 -di methyl -4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5- yl)acetate Synthesized from the title compound of PREPARATION 6 and tert-Butyl bromoacetate. Yield: 100%. Purity 100%.

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Abstract

La présente invention concerne des composés de formule (I), le procédé de préparation de tels composés et leur utilisation pour le traitement d'un état pathologique ou d'une maladie susceptible d'être amélioré par une activité antagoniste ou une inhibition des canaux TRPA1.
PCT/EP2015/057764 2014-04-11 2015-04-09 Nouveaux antagonistes de trpa1 Ceased WO2015155306A1 (fr)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017060488A1 (fr) 2015-10-09 2017-04-13 Almirall, S.A. Nouveaux antagonistes de trpa1
CN107840845A (zh) * 2016-09-19 2018-03-27 上海璃道医药科技有限公司 胺类化合物的新用途
CN110770237A (zh) * 2017-07-04 2020-02-07 萨内卡制药公司 制备吗啡烷化合物的方法
WO2021074198A1 (fr) * 2019-10-15 2021-04-22 Boehringer Ingelheim International Gmbh Nouveaux tétrazoles
CN112794860A (zh) * 2021-03-24 2021-05-14 上海肇钰医药科技有限公司 噁唑嘧啶酮酰胺类化合物或其可药用盐，制备方法及用途
WO2022058946A1 (fr) 2020-09-18 2022-03-24 Université Grenoble Alpes Inhibition du canal trpa1 astrocytaire comme nouvelle cible therapeutique neuroprotectrice dans les phases prodromales de la maladie d'alzheimer
WO2022058344A1 (fr) 2020-09-18 2022-03-24 Bayer Aktiengesellschaft Pyrido[2,3-d]pyrimidin-4-amines en tant qu'inhibiteurs de sos1
CN115023416A (zh) * 2019-12-13 2022-09-06 Z因子有限公司 用于治疗α1-抗胰蛋白酶缺乏症的4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺
EP4074317A1 (fr) 2021-04-14 2022-10-19 Bayer AG Dérivés de phosphore en tant que nouveaux inhibiteurs de sos1
IT202100015098A1 (it) 2021-06-09 2022-12-09 Flonext S R L Composto antagonista del canale trpa1 per uso in patologie degenerative della retina
US11655245B2 (en) 2018-03-19 2023-05-23 Genentech, Inc. Oxadiazole transient receptor potential channel inhibitors
WO2024056782A1 (fr) 2022-09-16 2024-03-21 Bayer Aktiengesellschaft Dérivés de pyrido[3,4-d]pyrimidine substitués par sulfone pour le traitement du cancer
WO2024079252A1 (fr) 2022-10-13 2024-04-18 Bayer Aktiengesellschaft Inhibiteurs de sos1
US12180223B2 (en) 2021-04-14 2024-12-31 Boehringer Ingelheim International Gmbh 3H,4H-thieno[2,3-d]pyrimidin-4-one derivatives as TRPA1 inhibitors
EP4255893A4 (fr) * 2020-12-04 2025-04-23 The Johns Hopkins University Composés et leur utilisation pour le traitement de la douleur neuropathique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996026187A1 (fr) * 1995-02-22 1996-08-29 Merck & Co., Inc. Antagonistes des recepteurs de fibrinogene
WO2010109328A1 (fr) * 2009-03-23 2010-09-30 Glenmark Pharmaceuticals, S.A. Dérivés d'isothiazolo-pyrimidinedione utiles comme modulateurs de la trpa1
WO2011132017A1 (fr) * 2010-04-19 2011-10-27 Glenmark Pharmaceuticals S.A. Dérivés de pyrido[3,4-d]pyrimidinyl acétamide comme modulateurs de trpa1

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996026187A1 (fr) * 1995-02-22 1996-08-29 Merck & Co., Inc. Antagonistes des recepteurs de fibrinogene
WO2010109328A1 (fr) * 2009-03-23 2010-09-30 Glenmark Pharmaceuticals, S.A. Dérivés d'isothiazolo-pyrimidinedione utiles comme modulateurs de la trpa1
WO2011132017A1 (fr) * 2010-04-19 2011-10-27 Glenmark Pharmaceuticals S.A. Dérivés de pyrido[3,4-d]pyrimidinyl acétamide comme modulateurs de trpa1

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GLENMARK PHARMACEUTICALS: "Glenmark's TRPA1 Antagonist 'GRC 17536' Shows Positive Data in a Proof of Concept Study", PRNEWSWIRE, 17 September 2014 (2014-09-17), XP055186940, Retrieved from the Internet <URL:http://www.prnewswire.com/news-releases/glenmarks-trpa1-antagonist-grc-17536-shows-positive-data-in-a-proof-of-concept-study-275445961.html> [retrieved on 20150430] *
JASON D'SOUZA ET AL: "Glenmark's novel molecule 'GRC 17536' for pain and respiratory conditions successfully completes Phase I trials in Europe", 14 February 2012 (2012-02-14), XP055186983, Retrieved from the Internet <URL:http://www.glenmarkpharma.com/GLN_NWS/PDF/Glenmark_GRC_17536_Phase_I_completion.pdf> [retrieved on 20150430] *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017060488A1 (fr) 2015-10-09 2017-04-13 Almirall, S.A. Nouveaux antagonistes de trpa1
CN107840845A (zh) * 2016-09-19 2018-03-27 上海璃道医药科技有限公司 胺类化合物的新用途
CN110770237A (zh) * 2017-07-04 2020-02-07 萨内卡制药公司 制备吗啡烷化合物的方法
US12202824B2 (en) 2018-03-19 2025-01-21 Genentech, Inc. Oxadiazole transient receptor potential channel inhibitors
US11655245B2 (en) 2018-03-19 2023-05-23 Genentech, Inc. Oxadiazole transient receptor potential channel inhibitors
CN114555601B (zh) * 2019-10-15 2024-04-02 勃林格殷格翰国际有限公司 新颖的四唑类
JP2022552520A (ja) * 2019-10-15 2022-12-16 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規なテトラゾール
CN114555601A (zh) * 2019-10-15 2022-05-27 勃林格殷格翰国际有限公司 新颖的四唑类
US12497401B2 (en) 2019-10-15 2025-12-16 Boehringer Ingelheim International Gmbh Substituted tetrazoles as TRPA1 inhibitors
JP7612682B2 (ja) 2019-10-15 2025-01-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規なテトラゾール
WO2021074198A1 (fr) * 2019-10-15 2021-04-22 Boehringer Ingelheim International Gmbh Nouveaux tétrazoles
CN115023416B (zh) * 2019-12-13 2024-04-02 森特萨制药(英国)有限公司 用于治疗α1-抗胰蛋白酶缺乏症的4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺
CN115023416A (zh) * 2019-12-13 2022-09-06 Z因子有限公司 用于治疗α1-抗胰蛋白酶缺乏症的4-((2-氧代吡啶-1(2H)-基)甲基)苯甲酰胺
WO2022058946A1 (fr) 2020-09-18 2022-03-24 Université Grenoble Alpes Inhibition du canal trpa1 astrocytaire comme nouvelle cible therapeutique neuroprotectrice dans les phases prodromales de la maladie d'alzheimer
FR3114235A1 (fr) 2020-09-18 2022-03-25 Université Grenoble Alpes Inhibition du canal trpa1 astrocytaire comme nouvelle cible therapeutique neuroprotectrice dans les phases prodromales de la maladie d’alzheimer
WO2022058344A1 (fr) 2020-09-18 2022-03-24 Bayer Aktiengesellschaft Pyrido[2,3-d]pyrimidin-4-amines en tant qu'inhibiteurs de sos1
EP4255893A4 (fr) * 2020-12-04 2025-04-23 The Johns Hopkins University Composés et leur utilisation pour le traitement de la douleur neuropathique
CN112794860A (zh) * 2021-03-24 2021-05-14 上海肇钰医药科技有限公司 噁唑嘧啶酮酰胺类化合物或其可药用盐，制备方法及用途
WO2022219035A1 (fr) 2021-04-14 2022-10-20 Bayer Aktiengesellschaft Utilisation de dérivés de phosphore en tant que nouveaux inhibiteurs de sos1
EP4074317A1 (fr) 2021-04-14 2022-10-19 Bayer AG Dérivés de phosphore en tant que nouveaux inhibiteurs de sos1
US12180223B2 (en) 2021-04-14 2024-12-31 Boehringer Ingelheim International Gmbh 3H,4H-thieno[2,3-d]pyrimidin-4-one derivatives as TRPA1 inhibitors
IT202100015098A1 (it) 2021-06-09 2022-12-09 Flonext S R L Composto antagonista del canale trpa1 per uso in patologie degenerative della retina
WO2024056782A1 (fr) 2022-09-16 2024-03-21 Bayer Aktiengesellschaft Dérivés de pyrido[3,4-d]pyrimidine substitués par sulfone pour le traitement du cancer
WO2024079252A1 (fr) 2022-10-13 2024-04-18 Bayer Aktiengesellschaft Inhibiteurs de sos1

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